A major goal of the Clinical Studies program is to elucidate the role of osteogenic cells in the generation of a variety of skeletal dysplasias. It was found that the metabolic activity of bone-forming cells is altered by a number of known mutations. In the first instance, in Osteogenesis imperfecta, our studies indicate that the presence of a type I collagen mutation has pleiotropic effects on cells-- altering not only collagen levels but also the levels of noncollagenous extracellular components, inducing error-checking machinery within the cell, and altering cellular proliferation. In McCune-Albright Syndrome which presents with severe fibrous dysplasia, there are missense mutations of the G protein, Gsa, leading to overproduction of cAMP. It was found that this protein is dramatically upregulated as marrow stromal fibroblasts (MSFs) mature into osteoblasts, and the effects of the mutations are manifested by abnormal cell-cell (hyperosteocytic bone), cell-matrix interactions (cellular retraction), and the formation of an abnormal bone matrix (high in anti- adhesive proteins, versican and osteonectin, low in adhesive proteins, osteopontin and bone sialoprotein). In addition to studying the role of osteogenic cells in skeletal diseases, another goal is to examine the ability of ex vivo expanded marrow stromal fibroblasts, MSFs, which contain osteogenic precursors, to regenerate normal bone tissue. The results have now identified the in vitro culture conditions as well as the transplantation vehicles that support complete bone regeneration by direct transplantation in a variety of experimental systems. Further studies are aimed at developing clinical protocols for bone regeneration in patients with a variety of skeletal defects.